Despite many major advances in AIDS research, including the development and optimization of potent anti- retroviral therapy (ART) that successfully suppresses virus replication in the majority of HIV-infected individuals, a treatment that can cure this deadly infection is still not available. Residual disease in ART-treated HIV-infected individuals consists mainly of (i) persistent immune abnormalities (including inflammation, limited CD4 T cell reconstitution, and premature immune senescence) which may ultimately lead to the so-called HIV- associated end-organ diseases, and (ii) the presence of persistent reservoirs of latently infected cells that are not affected by ART and are responsible for the rapid rebound of virus replication if ART is stopped. In the absence of a scalable treatment able to cure HIV infection, ART is a lifelong treatment that poses significant challenges in terms of costs and clinical safety. For these reasons, eradicating or at least functionally curing HIV infection would have a remarkable impact on global health. Residual inflammation may promote HIV persistence under ART by several mechanisms, including driving the infection of susceptible cells that sustain the persistence of the reservoir, and the exhaustion of HIV-specific antiviral immune responses. Thus, a vicious cycle may be triggered in which residual inflammation, ineffective antiviral immune responses, and HIV persistence are intimately connected. As such, there is a strong consensus that a cure for HIV infection will not be achieved through ART intensification alone, and that novel approaches aimed at limiting residual inflammation and improving antiviral immune responses may be needed. The overarching goal of this project is to explore the therapeutic potential of a novel, combined Interleukin (IL)-21 and Interferon-a (IFNa) intervention in ART-treated SIV-infected rhesus macaques (RMs). We propose that the sequential administration of IL-21 and IFNa is safe and will have a strong synergistic effect on HIV persistence by decreasing immune dysfunction and inflammation (via IL-21), as well as enhancing antiviral functions mediated by a number of host restriction factors (via IFNa). These hypotheses will be tested in Aims 1 and 2. Moreover, we are proposing a series of mechanistic studies aimed at defining the molecular and cellular effects of sequential administration of IL-21 and IFNa [Aim 3]. If our hypothesis is correct, the proposed studies will provide in vivo evidence of reduced inflammation, improved immune function, and decreased virus reservoirs following sequential IL-21 and IFNa treatment in the most relevant preclinical animal model of HIV infection and using two molecules that, as a single agent, are being tested (IL-21) or approved by the FDA (IFNa) for treatment of several human diseases. If successful, the proposed immune based intervention would then be tested in human clinical trials to assess its potential as a functional cure for HIV infection.